This PPG was started in September, 1982. The central theme is "the study of the role of vasoactive systems (autocrine, juxtacrine, paracrine and endocrine) in the regulation of renal function and blood pressure (BP) and mediation of end organ damage (EOD)". The general hypothesis to be tested is that in Ang ll-lnduced Hypertension there is a balance between systems that promote water and sodium retention, hypertension and EOD (Ang II, COX-2 products, ROS and inflammation), and systems that antagonize these effects (Ac- SDKP, activation of the Ang II type 2 receptor, kinins, NO, eicosanoids and the newly discovered cross-talk between the connecting tubule and the afferent arteriole). Alterations of this balance in favor of the former are responsible for retention of water and sodium and development of hypertension and EOD, while alterations of this balance in favor of the latter have therapeutic effects. We will use molecular, physiological, and pharmacological approaches to study vasoactive systems at the subcellular, cellular, and isolated organ levels and in Ang ll-induced hypertension in rabbits, rats and various transgenic mice. In project I we will study whether in Ang II induced hypertension, a novel peptide (Ac-SDKP) alters the balance between systems that promote and oppose EOD in favor of the latter, thus preventing and regressing this process. In project II we will study whether in Ang ll-induced hypertension cardiac damage and dysfunction are antagonized by activation of the AT2 receptor via kinins and NO. In project III we will study whether in Ang ll-induced hypertension, expression of COX-2 and PGE2 production, acting through its EP4 receptor, promotes the development of cardiovascular disease. In project IV, we will study whether in Ang ll-induced hypertension, the renal microcirculation is regulated by a novel mechanism, cross-talk between the connecting tubule and the afferent arteriole, that antagonizes the vasoconstrictor effect of Ang II. In project V, we will study whether in Ang ll-induced hypertension renal function is altered by oxidative stress in the nephron, which causes a decrease in NO and an increase in sodium absorption. Four cores (Administrative, Analytical and Morphological, Mutant Mouse and Biostatistics) will support and facilitate the scientific efforts of the investigators. The PPG provides integration of our efforts, collaboration and sharing of ideas and expertise, thus accelerating acquisition of knowledge on the pathogenesis of hypertension and EOD.